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Inhibitors of phosphodiesterases in infertility

a technology of phosphodiesterases and infertility, which is applied in the field of inhibitors of phosphodiesterases in infertility, can solve the problems of producing ovarian hyperstimulation syndrome (ohss), affecting the normal development of ovarian follicles, and affecting the development of ovaries, so as to stimulate follicular growth and maturation, stimulate follicular growth, and increase follicle maturation

Inactive Publication Date: 2006-12-26
LAB SERONO SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention provides a method for increasing follicle maturation and stimulating ovarian follicular growth in a mammal by administering a phosphodiesterase (PDE) inhibitor. The PDE inhibitor can be used alone or in combination with other agents such as gonadotropin hormones or phosphodiesterase hormones. The PDE inhibitor can be administered starting in the stimulatory phase, before ovulation, and is preferably stopped before or on the day when ovulation is started. The medicament can be used for stimulating ovarian follicular growth in a patient undergoing assisted reproductive technologies. The PDE inhibitor can be administered simultaneously, separately, or sequentially with FSH or an agent having FSH activity. The invention also provides a method for preparing a medicament for stimulating ovarian follicular growth by administering a PDE inhibitor and a gonadotropin hormone or phosphodiesterase hormone. The PDE inhibitor can be selected from certain compounds such as sildenafil, dipyridamole, and zaprinast. The invention provides a method for increasing follicle maturation and stimulating ovarian follicular growth for improving assisted reproductive technologies."

Problems solved by technology

Despite the fact that protocols such as those described above have been used in clinical protocols for a number of years, these protocols are not without some significant disadvantages.
The daily injections can cause patient discomfort and inconvenience and can be relatively costly.
Such large doses and daily administration has the related risk of producing ovarian hyperstimulation syndrome (OHSS), which in severe cases may be life-threatening.
There are other additional side-effects from the gonadotropin preparations including weight gain, bloating, nausea, vomiting, the time involved with the monitoring process, and the unknown long-term cancer risk.
These hormone treatment regimens will become even more of a problem when IVF is offered to perfectly normal women in these programs due to infertility problems associated with the males partner's poor sperm quality.
Thus, there are problems associated with the current protocols used in oocyte generation for IVF.
However, while in animals in vitro maturation (IVM) has become an efficient method for producing oocytes for IVF, the recorded success rates for clinical human IVM have been low.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Ovulation Induction Using Various Pde Inhibitors in Combination with Low-dose FSH

[0144]Experiments were conducted according to the In Vivo Rat Follicle Maturation Assay, described above. In one experiment, ovaries were harvested from rats at midday of the second day of treatment for histological analysis, prior to the last set of injections. These rats received only the first three doses of FSH and test compound prior to euthanasia and organ harvest. The secondary follicles were evaluated by counting the total number of secondary follicles: including both small follicles (those at any intermediate stage of maturation, having a multilayered granulosa with the first, scattered vacuoles, but without an antrum) and antral follicles (those having antral dilation, with an external diameter of around 500 microns, or higher, with or without thinning of the granulosa cell layer). The antral follicles (≧500 mcm) were also counted separately.

Data Analysis

[0145]The proportion of ovulating anima...

example 2

Induction of cAMP Using Various PDE Inhibitors in Combination with Low-dose FSH

[0172]In addition to the evaluation of rat granulosa cells, produced as described above, in order to measure cAMP in cell lines, JC-410 porcine granulosa cells were used. These cells were obtained from Dr. Jorge Chedrese (University of Saskatchewan). The cells were maintained in DMEM / F12 supplemented with 5% newborn calf serum (Gibco) and 5 μg / ml of insulin (Gibco). Stable cell lines were established by transfecting the cDNAs 1635 for the human LH and FSH receptors into the cells using standard transfection techniques and selection with 300 μg / ml of Geneticin (Gibco). Following selection, the cells were maintained in the same concentration of Geneticin. For cAMP determinations, the cells were plated at a density of 25,000 cells per well, in 96 well plates, one day prior to the assay. The following day, the cells were stimulated for 1 hour with increasing doses of the inhibitor molecules in the presence, o...

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Abstract

The present invention is directed to methods of increasing oocyte production in a mammal. More specifically, the specification describes methods and compositions for inducing follicular maturation using a PDE inhibitor. The inhibitor may be used alone at high doses. Alternatively, the follicular maturation is achieved by combining a low dose of FSH with the PDE inhibitor treatment.

Description

[0001]This application claims the benefit of U.S. Provisional Application No. 60 / 458,955, filed Apr. 1, 2003, U.S. Provisional Application No. 60 / 470,434, filed May 15, 2003, U.S. Provisional Application No. 60 / 540,301, filed Jan. 28, 2004, and U.S. Provisional Application No. 60 / 544,003, filed Feb. 12, 2004, each of which is incorporated by reference herein in its entirety.FIELD OF INVENTION[0002]The present invention is generally directed to reproductive biology and assisted reproductive technologies (ART), such as controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF). More specifically, the present invention is directed to methods and compositions for inducing follicle maturation in vivo using one or more phosphodiesterase inhibitors either alone or in combination with one or more gonadotropins, including the stimulation of follicle maturation for purposes such as ovulation induction (OI). In addition, the invention is directed to methods and compositions for...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/00A61K31/505A61K31/517A61K31/519A61K31/53A61K38/09A61K38/24A61K45/06
CPCA61K31/505A61K31/517A61K31/519A61K31/53A61K38/09A61K38/24A61K45/06A61K2300/00A61P15/00A61P15/08A61P43/00A61K45/00
Inventor PALMER, STEPHEN S.MCKENNA, SEAN D.ARKINSTALL, STEPHEN J.ESHKOL, ALIZAMACNAMEE, MICHAEL C.
Owner LAB SERONO SA
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